(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabic yclo[3.1.0]hexane-2-carboxamide

[0001] Priority is claimed of European patent application no. 21 208 045.1 that was filed on November 12, 2021.

[0002] The invention relates to a process for the synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3. 1 ,0]hexane-2 -carboxamide .

[0003] (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -3-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0 ]hexane-2 -carboxamide, also known as PF-07321332 and INN Nirmatrelvir, is an experimental antiviral drug which acts as an orally active 3CL protease inhibitor. It is a covalent inhibitor, binding directly to the catalytic cysteine (Cysl45) residue of the enzyme. A combination with ritonavir will be available under the tradename (Paxlovid®).

[0004] The synthesis approach of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -3- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide as shown in Figure 1 was published in D.R. Owen et al., Science 10.1126/science.abl4784 (2021). This linear synthesis has six reaction steps with relatively high yield in some steps, but relatively low yield in the other steps. The acylation step using ethyl trifluoroacetate (4) is a critical step, since the yield of the conversion is low. Additionally, the last step of the synthesis converting the amide group of (18) into a nitrile group using Burgess reagent is critical as well. The reaction conversion of the amide group to the nitrile group is relatively low (75%). Consequently, because of these two critical steps, the complete synthesis yield is low (about 50%).

[0005] It is an object of the invention to provide a synthetic route for (lR,2S,5S)-N-((S)-l-cyano-2- ((S)-2-oxopyrrolidin-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3 . 1.0] hexane -2 -carboxamide having advantages compared to the known synthetic route.

[0006] This object has been achieved by the subject-matter of the patent claims.

[0007] It has been surprisingly found that the drawbacks of the known synthetic route can be overcome when the nitrile group is formed in an early stage of the overall synthesis where the introduction of the group is easily carried out. In subsequent steps, the peptide bonds are formed using a convergent synthesis approach.

[0008] A first aspect of the invention relates to a process for the synthesis of (1R,2S,5S)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl -2-(2,2,2-trifluoroacetamido)butanoyl)- 6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -carboxamide according to general formula (I), the process comprising the steps of:

(a) providing (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile according to general formula

(b) providing (lR,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid or an activated form thereof according to general formula (III)

(Ill); wherein X is hydroxyl or halogen, preferably Cl;

(c) reacting the compound according to general formula (II) with the compound according to general formula (III) thereby obtaining (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -6,6- dimethyl-3 -azabicyclo [3.1.0]hexane-2 -carboxamide according to general formula (IV)

(d) optionally, purifying the compound according to general formula (IV) obtained in step (c); (e) providing (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid or an activated form thereof according to general formula (V)

(V); wherein Y is hydroxyl or halogen, preferably Cl;

(f) reacting the compound according to general formula (IV) with the compound according to general formula (V) thereby obtaining the compound according to general formula (I); and

(g) optionally, purifying the compound according to general formula (I) obtained in step (f).

[0009] Steps (d) and (g) are optional. Preferably, process steps (a) through (g) are performed in alphabetical order, whereas it is contemplated that steps (a), (b) and (e) may be performed in any order or simultaneously.

Step (a)

[0010] (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile according to general formula (II) provided in step (a) can be prepared by methods and from starting materials that are known to the skilled person.

[0011] Preferably, step (a) of the process according to the invention involves the substeps of

(al) providing methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoate according to general formula (Ila)

(a2) deblocking the tert-butoxycarbonyl group of the compound according to general formula (Ila) thereby obtaining methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate according to general formula (lib) (lib);

(a3) reducing the ester group of the compound according to general formula (lib) thereby obtaining (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanal according to general formula (lie)

(a4) converting the aldehyde group of the compound according to general formula (lie) into a nitrile group thereby obtaining the (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile according to general formula (II)

[0012] Preferably, substep (a3) is carried out at a temperature below -18°C, preferably at about -78°C.

[0013] Preferably, substep (a3) involves contacting the compound according to general formula (lib) with diisobutyl aluminum hydride (DIBAL) in dichloromethane in the presence of pyridinium chlorochromate (see e.g. J. Org. Chem. 1985, 50, 4417-4418).

[0014] Preferably, substep (a4) involves reacting the compound according to general formula (lie) with ammonia in THF in the presence of iodine (see e.g. Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 3141 - 3144).

[0015] (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3- yl)propanoate according to general formula (Ila) is commercially available.

[0016] Alternatively, (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile according to general formula (II) can be prepared according any other synthetic route from various starting materials.

Step (b)

[0017] (lR,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxyl ic acid or an activated form thereof according to general formula (III) provided in step (b) is also known from the literature and can be prepared by methods and from starting materials that are known to the skilled person. The methyl ester hydrochloride (CAS 565456-77-1) is commercially available. For example, the acid chloride can be obtained by reacting the carboxylic acid with SOCL, SO2CI2, PCI5, and the like.

Step (c) [0018] Preferably, step (c) of the process according to the invention is carried out in an organic solvent. Preferably, the compound according to general formula (II) and the compound according to general formula (III) are both completely dissolved in the organic solvent. Preferably, the organic solvent is not or hardly miscible with water.

[0019] In preferred embodiments, the organic solvent is selected from the group consisting of

- halogenated hydrocarbons, preferably dichloromethane or dichloroethane;

- aromatic hydrocarbons, preferably toluene;

- aliphatic hydrocarbons, preferably hexane or heptane;

- cycloaliphatic hydrocarbons, preferably cyclopentane or cyclohexane;

- ethers, preferably tert-butyl methyl ether (TBME), tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), dioxanes, or dimethyl ether (DME);

- esters, preferably ethyl acetate;

- nitriles, preferably acetonitrile;

- amides, preferably dimethyl formamide (DMF) or dimethyl acetamide (DMA); and

- mixtures thereof.

[0020] Dichloromethane is particularly preferred.

[0021] Preferably, step (c) of the process according to the invention is carried out in the presence of an organic base.

[0022] In preferred embodiments, the organic base is selected from the group consisting of

- trialkylamines, preferably trimethylamine , triethylamine or diisopropylethyl amine (DIPEA);

- imidazoles, preferably imidazole or 1 -methylimidazole;

- pyridines, preferably pyridine, 2,6-lutidine, or dimethylamino pyridine;

- morpholines, preferably N-methyhnorpholine (NMM); and mixtures thereof.

[0023] Triethylamine is particularly preferred. [0024] In preferred embodiments, the organic base is employed in a molar proportion of about 1 to about 5 moles per mole of the compound according to general formula (IV); preferably up to about 3 moles per mole of the compound according to general formula (IV).

[0025] Preferably, step (c) of the process according to the invention is carried out at a temperature within the range of from about -20 °C to about 30 °C, preferably from about -10 °C to about 20 °C, more preferably from about -10 °C to about 10 °C.

[0026] Preferably, step (c) of the process according to the invention is carried out for a reaction time of up to about 24 hours, preferably in the range of from about 1 hour to about 12 hours.

[0027] In preferred embodiments, the molar ratio of the compound according to general formula (III) to the compound according to general formula (II) is within the range of from 1 : 1 to 1.5 : 1.

[0028] Preferably, step (c) of the process according to the invention is carried out in the presence of an activation reagent.

[0029] In preferred embodiments, the activation reagent is selected from the group consisting of dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), I-ethyl-3-(3-dimethylaminopropyl)car- bodiimide (EDC), cyclohexyl isopropyl carbodiimide (CIC), I . I '-carbonyldiimidazol (CDI), 2-(lH-ben- zotriazole-I-yl)-I,I,3,3-tetramethylaminium tetrafluoroborate (TBTU), and benzotriazol -1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0030] Preferably, step (c) of the process according to the invention is carried out in the presence of a catalyst. 1 -Hydroxy benzotriazole (HOBt) is particularly preferred.

[0031] Preferably, in step (c) of the process according to the invention, the yield of the compound according to general formula (IV) is at least 85%, preferably at least 90%.

Step (d)

[0032] Preferably, optional step (d) of the process according to the invention involves the substeps of

(dl) adding water to the reaction mixture thereby obtaining an organic phase and an aqueous phase;

(d2) extracting the compound according to general formula (IV) in the organic phase;

(d3) separating the organic phase from the aqueous phase; and (d4) evaporating the solvent from the organic phase thereby isolating the compound according to general formula (IV).

Step (e)

[0033] (S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid or an activated form thereof according to general formula (V) provided in step (e) is also known from the literature and can be prepared by methods and from starting materials that are known to the skilled person. For example, the acid chloride can be obtained by reacting the carboxylic acid with SOCh, SO2CI2, PCI5, and the like.

[0034] Preferably, step (e) of the process according to the invention involves the substep of

(el) reacting trifluoroacetic acid chloride according to general formula (Va) with (S)-3,3-dimethyl-2 -amino -butanoic acid according to general formula (Vb) or a carboxy-protected form thereof thereby obtaining the compound according to general formula (V).

[0035] These starting materials are commercially available.

Step (f)

[0036] Preferably, step (f) of the process according to the invention is carried out in an organic solvent. Preferably, the compound according to general formula (IV) and the compound according to general formula (V) are both dissolved in the organic solvent. Preferably, the organic solvent is not or hardly miscible with water.

[0037] In preferred embodiments, the organic solvent is selected from the group consisting of

- halogenated hydrocarbons, preferably dichloromethane or dichloroethane;

- aromatic hydrocarbons, preferably toluene;

- aliphatic hydrocarbons, preferably hexane or heptane; - cycloaliphatic hydrocarbons, preferably cyclopentane or cyclohexane;

- ethers, preferably tert-butyl methyl ether (TBME), tetrahydrofuran (THF), methyl tetrahydrofuran (MeTHF), dioxanes, or dimethyl ether (DME);

- esters, preferably ethyl acetate;

- nitriles, preferably acetonitrile;

- amides, preferably dimethyl formamide (DMF) or dimethyl acetamide (DMA); and

- mixtures thereof.

[0038] Dichloromethane is particularly preferred.

[0039] Preferably, step (f) of the process according to the invention is carried out in the presence of an organic base.

[0040] In preferred embodiments, the organic base is selected from the group consisting of

- trialkylamines, preferably trimethylamine , triethylamine or diisopropylethyl amine (DIPEA);

- imidazoles, preferably imidazole or 1 -methylimidazole;

- pyridines, preferably pyridine, 2,6-lutidine, or dimethylamino pyridine;

- morpholines, preferably N-methyhnorpholine (NMM); and

- mixtures thereof.

[0041] Triethylamine is particularly preferred.

[0042] In preferred embodiments, the organic base is employed in a molar proportion of about 1 to about 5 moles per mole of the compound according to general formula (I); preferably up to about 3 moles per mole of the compound according to general formula (I).

[0043] Preferably, step (f) of the process according to the invention is carried out at a temperature within the range of from about -20 °C to about 30 °C, preferably from about -10 °C to about 20 °C, more preferably from about -10 °C to about 10 °C.

[0044] Preferably, step (f) of the process according to the invention is carried out for a reaction time of up to about 24 hours, preferably in the range of from about 1 hour to about 12 hours. [0045] In preferred embodiments, the molar ratio of the compound according to general formula (V) to the compound according to general formula (IV) is within the range of from 1 : 1 to 1.5 : 1.

[0046] Preferably, step (f) of the process according to the invention is carried out in the presence of an activation reagent.

[0047] In preferred embodiments, the activation reagent is selected from the group consisting of dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)car- bodiimide (EDC), cyclohexyl isopropyl carbodiimide (CIC), I . I '-carbonyldiimidazol (CDI), 2-(lH-ben- zotriazole-l-yl)-l,l,3,3-tetramethylaminium tetrafluoroborate (TBTU), and benzotriazol -1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate (BOP).

[0048] Preferably, step (f) of the process according to the invention is carried out in the presence of a catalyst. 1 -Hydroxy benzotriazole (HOBt) is particularly preferred.

[0049] Preferably, in step (f) of the process according to the invention the yield of the compound according to general formula (I) is at least 85%, preferably at least 90%.

Step (g)

[0050] Preferably, optional step (g) of the process according to the invention involves the substeps of

(g 1) adding water to the reaction mixture thereby obtaining an organic phase and an aqueous phase;

(g2) extracting the compound according to general formula (I) in the organic phase;

(g3) separating the organic phase from the aqueous phase; and

(g4) evaporating the solvent from the organic phase thereby isolating the compound according to general formula (I).

[0051] A preferred embodiment of the synthetic route according to the invention is illustrated in Figure 2.

[0052] Further aspects of the invention relate to crystalline forms of (lR,2S,5S)-N-((S)-l-cyano-2-((S)- 2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-tri fluoroacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir).

[0053] New crystalline forms of Nirmatrelvir are interesting, as compared to known crystalline forms they can have certain advantages. Different physical properties can cause different crystalline forms of the same drug to have largely different processing and storage performance. Such physical properties include, for example, thermodynamic stability, crystal morphology [form, shape, structure, particle size, particle size distribution, degree of crystallinity, color], ripple behavior, flowability, density, bulk density, powder density, apparent density, vibrated density, depletability, emptyability, hardness, deformability, grindability, compressability, compactability, brittleness, elasticity, caloric properties [particularly melting point], solubility [particularly equilibrium solubility, pH dependence of solubility], dissolution [particularly dissolution rate, intrinsic dissolution rate], reconstitutability, hygroscopicity, tackiness, adhesiveness, tendency to electrostatic charging, and the like. In addition, different chemical properties can cause different crystalline forms of the same drug to have largely different performance properties. For example, a crystalline form having a low hygroscopicity (relative to other crystalline forms) can have superior chemical stability and longer shelf-life stability.

[0054] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5 XRPD peaks selected from 6.478, 6.715, 8.918, 10.589, 11.066, 11.163, 11.441, 11.637, 12.375, 12.508, 12.689, 14.058, 16.509, 16.961, 17.198, 18.483, 19.970, 20.260, 21.445, 22.396, 23.574, 25.369, and 29.653 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0055] Such a crystalline form can be obtained from solutions of Nirmatrelvir in methanol at room temperature by adding methyl isobutyl ketone and stirring at room temperature.

[0056] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7, even more preferably at least 8, most preferably at least 9, and in particular at least 10 XRPD peaks selected from 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222, 15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193, 20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, and 29.752 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0057] Such a crystalline form can be obtained from solutions of Nirmatrelvir in acetone at 50°C by adding tert-butyl methyl ether and stirring at room temperature. [0058] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7, even more preferably at least 8, most preferably at least 9, and in particular at least 10 XRPD peaks selected from 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222, 15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193,

20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, and 29.752 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0059] Such a crystalline form can be obtained from solutions of Nirmatrelvir in methanol at room temperature by adding tert-butyl methyl ether and stirring at room temperature.

[0060] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7, even more preferably at least 8, most preferably at least 9, and in particular at least 10 XRPD peaks selected from 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222,

15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193, 20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, and 29.752 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0061] Such a crystalline form can be obtained from solutions of Nirmatrelvir in tetrahydrofuran at room temperature by adding tert-butyl methyl ether and stirring at room temperature.

[0062] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7 XRPD peaks selected from 6.031, 11.024, 11.509, 11.957, 12.498, 15.964, and 20.291 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0063] Such a crystalline form can be obtained from solutions of Nirmatrelvir in acetone at 50°C by adding ethyl acetate and stirring at room temperature. [0064] In preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-ox- opyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluo roacetamido)butanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7 XRPD peaks selected from 6.031, 11.024, 11.509, 11.957, 12.498, 15.964, and 20.291 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0065] Such a crystalline form can be obtained from solutions of Nirmatrelvir in methanol at room temperature by adding ethyl acetate and stirring at room temperature.

[0066] In particularly preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cyano-2- ((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2, 2-trifluoroacetamido)butanoyl)-6,6-dime- thyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (INN Nirmatrelvir) has XRPD peaks at 8.9, 14.1, 21.4, and 23.6 20; preferably additionally one or more XRPD peaks selected from 6.7, 11.2, 11.6, 12.4, 18.5, 20.0, and 25.4 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0067] In further particularly preferred embodiments, the crystalline form of (lR,2S,5S)-N-((S)-l-cy- ano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2 -(2,2,2-trifluoroacetamido)butanoyl)-6,6- dimethyl-3 -azabicyclo [3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has at least 3, preferably at least 4, more preferably at least 5, still more preferably at least 6, yet more preferably at least 7 XRPD peaks at 7.2, 10.2, 13.0, 13.8, 14.4, 15.2, 15.5, 16.2, 16.3, 17.9, 19.2, 19.4, 20.5, 21.0, 22.1, 23.0, 23.9, 24.5, and 28.6 20; preferably additionally one or more XRPD peaks selected from 12.2, 18.7, 20.2, and 25.6 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0068] In still further particularly preferred embodiments, the crystalline form of (1R,2S,5S)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl -2-(2,2,2-trifluoroacetamido)butanoyl)- 6, 6-dimethyl-3-azabicyclo[3.1.0]hexane-2 -carboxamide (INN Nirmatrelvir) has XRPD peaks at 6.0, 12.5 and 20.3 20; preferably additionally one or more XRPD peaks selected from 11.0, 11.5, 12.0, and 16.0 20 (Cuk _a , 23°C, in each case values as 20 with an error margin of ±0.2 20).

[0069] The following examples further illustrate the invention but are not to be construed as limiting its scope.

Example 1 - synthesis of (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -6,6-dimethyl- 3 -azabicyclo [3 , 1 ,0]hexane-2 -carboxamide

[0070] (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanenitrile (0.306g, 2 mmol) was suspended in 8 ml of dichloromethane and then 0.2 ml of triethylamine were added. Then, (lR,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2 -carboxylic acid chloride hydrochloride (0.42 g, 2 mmol) was slowly added at 0°C and the mixture was stirred at room temperature for 6 hours. Then the solvent was evaporated and the product was isolated as residue (1 g, around 50% content of the title product). Since the intermediate is unstable, for conversion that follows also direct reaction mixture without evaporation can be used.

Example 2 - synthesis of (lR.2S.5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -3-((S)-3,3-di- methyl -2 -(2.2.2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyc lo[3.1.0]hexane-2 -carboxamide (Nirmatrelvir)

[0071] (lR,2S,5S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -6,6-dimethyl-3-azabicy- clo[3.1.0]hexane-2 -carboxamide (2 mmol in form of residue or mixture in dichloromethane) was suspended in dichloromethane (5ml) and then 0.3 ml of trimethylamine was added and after that (S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid chloride (0.49 g, 2mmol) was slowly added at 0°C. The mixture was stirred at room temperature for 6 hours. To the mixture water was added and the phases were separated. The washing was repeated two times. The solvent was evaporated and the product was isolated by suspending in mixture tetrahydrofuran /tert-butyl methyl ether (1: 1) (mp: 188 - 193 °C).

[0072] For crystallization different mixtures were tested: [0073] A. 50 mg of Nirmatrelvir were dissolved in 100 pl of methanol at room temperature. Then 200 pl of methyl isobutyl ketone were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.478, 6.715, 8.918, 10.589, 11.066, 11.163, 11.441, 11.637, 12.375, 12.508, 12.689, 14.058, 16.509, 16.961, 17.198, 18.483, 19.970, 20.260, 21.445, 22.396, 23.574, 25.369, 29.653).

[0074] B. 50 mg of Nirmatrelvir were dissolved in 100 pl of acetone at 50 °C. Then 200 pl of tert-butyl methyl ether were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222, 15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193, 20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, 29.752).

[0075] C. 50 mg of Nirmatrelvir were dissolved in 100 pl of methanol at room temperature. Then 200 pl of tert-butyl methyl ether were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222, 15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193, 20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, 29.752).

[0076] D. 50 mg of Nirmatrelvir were dissolved in 100 pl of tetrahydrofuran at room temperature. Then 200 pl of tert-butyl methyl ether were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.361, 6.949, 7.229, 10.238, 10.649, 11.055, 11.519, 12.011, 12.245, 12.747, 13.042, 13.792, 14.366, 15.222, 15.524, 15.892, 16.166, 16.296, 16.564, 16.977, 17.288, 17.925, 18.693, 19.150, 19.399, 20.193, 20.523, 20.969, 22.071, 22.363, 23.032, 23.936, 24.512, 25.572, 28.553, 29.752).

[0077] E. 50 mg of Nirmatrelvir were dissolved in 100 pl of acetone at 50 °C. Then 200 pl of ethyl acetate were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.031, 11.024, 11.509, 11.957, 12.498, 15.964, 20.291).

[0078] F. 50 mg of Nirmatrelvir were dissolved in 100 pl of methanol at room temperature. Then 200 pl of ethyl acetate were added. The suspension was stirred for about 1 hour at room temperature. Then the mixture was concentrated under reduced pressure. On the residue XRPD was performed (absorption peaks: 6.031, 11.024, 11.509, 11.957, 12.498, 15.964, 20.291).